Azahelicene Superbases as MAILD Matrices for Acidic Analytes

Fast metabolite profiling, imaging and drug analysis is an indispensable tool nowadays in the discovery of biomarkers and disease diagnostic applications. Matrix-assisted laser desorption/ionisation (MALDI), developed in the late eighties, represents one high-throughput method. Initially used for the mass spectrometric analyses of large biomolecules, for example, proteins, peptides and oligosaccharides, recently it has frequently been used to analyse small molecules. However, conventional MALDI matrices (e.g. , 2,5-dihydroxybenzoic or a-cyanohydroxycinnamic acids) produce a significant background of interfering peaks within the low-mass region; thus limiting the usefulness of MALDI-MS techniques in the analysis of low-molecular-mass analytes (Mr<500 Da). [3] To extend the MALDI-MS technique to include small-molecule analysis and to utilise this fast high-throughput screening technique for metabolomic studies, we have recently developed a novel approach. It is based on the usage of superbasic UV-absorbing matrices that do not undergo facile gasphase deprotonation. Accordingly, no interfering anions are generated during the measurements. In contrast to the MALDI technique, ionisation is completed in a solution, if an acidic analyte is mixed with a super base; thus forming an ion pair. Such a phenomenon was explained by the Bronsted–Lowry acid–base theory and the new method was coined “matrix-assisted ionisation/laser desorption” (MAILD). Specifically, 1,8-bis(dimethylamino)naphthalene (DMAN; a “proton sponge”) was shown to obviate the problem of low-mass-region interference in MALDI-TOF/MS spectra of low-molecular-weight compounds at physiologically relevant concentrations. The same principle was applied to the positive-ion mode of MAILD by using 2naphtholsulfonic acid. Recently, it was realised by us and others that DMAN might desorb under experimental conditions (10 6 mbar) to form deposits in an ion source; these deposits might result in the appearance of interfering peaks in MS spectra. To eliminate this troublesome drawback, we have been searching for alternative MAILD matrices either by modifying the structure of DMAN or by exploring other types of organic superbases.